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MicroRNAs in Cerebral Ischemia

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Abstract

Pathogenesis of cerebral ischemia has so far been described in the context of proteins and the pathways that they regulate. The discovery of biomarkers has also been focussed mainly on proteins and to some extent on the mRNAs that encode them. The knowledge on the role of microRNAs in understanding the pathogenesis of cerebral ischemia is still at its infancy. In this study, using rat models subjected to middle cerebral artery occlusion, we have profiled the microRNAs at different reperfusion times (0 to 48 h) to understand the progression of cerebral ischemia. We have also attempted to correlate the expression of microRNAs to treatment with an NMDA antagonist (MK801) and to protein expression with the hope of demonstrating the potential use of microRNAs as early biomarkers of stroke.

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References

  1. Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav. 2007;87:79–197.

    Article  Google Scholar 

  2. Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007;54:34–66.

    Article  CAS  PubMed  Google Scholar 

  3. Endres M, Dirnagl U. Ischemia and stroke. Adv Exp Med Biol. 2002;513:455–73.

    CAS  PubMed  Google Scholar 

  4. Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis. 2004;19:151–67.

    Article  CAS  PubMed  Google Scholar 

  5. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology. 2008;55:310–8.

    Article  CAS  PubMed  Google Scholar 

  6. Hergenroeder G, Redell JB, Moore AN, Dubinsky WP, Funk RT, Crommett J, et al. Identification of serum biomarkers in brain-injured adults: potential for predicting elevated intracranial pressure. J Neurotrauma. 2008;25:79–93.

    Article  PubMed  Google Scholar 

  7. Laterza OF, Modur VR, Crimmins DL, Olander JV, Landt Y, Lee JM, et al. Identification of novel brain biomarkers. Clin Chem. 2006;52:1713–21.

    Article  CAS  PubMed  Google Scholar 

  8. Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 2008;39:959–66.

    Article  CAS  PubMed  Google Scholar 

  9. Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD, Wang CW, et al. Expression profile of MicroRNAs in young stroke patients. PLoS ONE. 2009;4:e7689.

    Article  PubMed  Google Scholar 

  10. Laterza OF, Lim L, Garrett-Engele PW, Vlasakova K, Muniappa N, Tanaka WK, et al. Plasma microRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem. 2009;55:1977–83.

    Article  CAS  PubMed  Google Scholar 

  11. Catalucci D, Gallo P, Condorelli G. MicroRNAs in cardiovascular biology and heart disease. Circ Cardiovasc Genet. 2009;2:402–8.

    Article  CAS  PubMed  Google Scholar 

  12. Crosby ME, Devlin CM, Glazer PM, Calin GA, Ivan M. Emerging roles of microRNAs in the molecular responses to hypoxia. Curr Pharm Des. 2009;15:3861–6.

    Article  CAS  PubMed  Google Scholar 

  13. Fasanaro P, Greco S, Ivan M, Capogrossi MC, Martelli F. microRNA: emerging therapeutic targets in acute ischemic diseases. Pharmacol Ther. 2010;125:92–104.

    Article  CAS  PubMed  Google Scholar 

  14. Buchan AM, Slivka A, Xue D. The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke. Brain Res. 1992;574:171–7.

    Article  CAS  PubMed  Google Scholar 

  15. Shuaib A, Yang Y, Nakada MT, Li Q, Yang T. Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab. 2002;22:215–22.

    Article  CAS  PubMed  Google Scholar 

  16. Yang Y, Li Q, Wang CX, Jeerakathil T, Shuaib A. Dose-dependent neuroprotection with tiagabine in a focal cerebral ischemia model in rat. NeuroReport. 2000;11:2307–11.

    Article  CAS  PubMed  Google Scholar 

  17. Brunt J, Hansen R, Jamieson DJ, Austin B. Proteomic analysis of rainbow trout (Oncorhynchus mykiss, Walbaum) serum after administration of probiotics in diets. Vet Immunol Immunopathol. 2008;121:199–205.

    Article  CAS  PubMed  Google Scholar 

  18. Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, et al. The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res. 2005;33(Database issue):D284–8.

    Article  CAS  PubMed  Google Scholar 

  19. Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 2009;29:675–87.

    Article  CAS  PubMed  Google Scholar 

  20. Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab. 2010;30:92–101.

    Article  PubMed  Google Scholar 

  21. Nakanishi K, Nakasa T, Tanaka N, Ishikawa M, Yamada K, Yamasaki K, et al. Responses of microRNAs 124a and 223 following spinal cord injury in mice. Spinal Cord. 2010;48:192–6.

    Article  CAS  PubMed  Google Scholar 

  22. Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun. 2010;394:184–8.

    Article  CAS  PubMed  Google Scholar 

  23. Felli N, Pedini F, Romania P, Biffoni M, Morsilli O, Castelli G, et al. MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis. Haematologica. 2009;94:479–86.

    Article  CAS  PubMed  Google Scholar 

  24. Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125–9.

    Article  CAS  PubMed  Google Scholar 

  25. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138:592–603.

    Article  CAS  PubMed  Google Scholar 

  26. Cochrane DR, Howe EN, Spoelstra NS, Richer JK. Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J Oncol. 2010;2010:821717.

    PubMed  Google Scholar 

  27. Bredenkamp N, Seoighe C, Illing N. Comparative evolutionary analysis of the FoxG1 transcription factor from diverse vertebrates identifies conserved recognition sites for microRNA regulation. Dev Genes Evol. 2007;217(3):227–33.

    Article  CAS  PubMed  Google Scholar 

  28. Zheng H, Zeng Y, Zhang X, Chu J, Loh HH, Law PY. mu-Opioid receptor agonists differentially regulate the expression of miR-190 and NeuroD. Mol Pharmacol. 2010;77(1):102–9.

    Article  CAS  PubMed  Google Scholar 

  29. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.

    Article  PubMed  Google Scholar 

  30. Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, et al. Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev. 2009;23(5):561–74.

    Article  CAS  PubMed  Google Scholar 

  31. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.

    Article  CAS  PubMed  Google Scholar 

  32. Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27:6667–78.

    Article  CAS  PubMed  Google Scholar 

  33. Chan SY, Loscalzo J. MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle. 2010;9(6):1072–83.

    Article  CAS  Google Scholar 

  34. Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer. 2007;6:60.

    Article  PubMed  Google Scholar 

  35. Selcuklu SD, Donoghue MT, Spillane C. miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans. 2009;37:918–25.

    Article  CAS  PubMed  Google Scholar 

  36. Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008;68(19):8164–72.

    Article  CAS  PubMed  Google Scholar 

  37. Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324:1710–3.

    Article  CAS  PubMed  Google Scholar 

  38. Fraisl P, Mazzone M, Schmidt T, Carmeliet P. Regulation of angiogenesis by oxygen and metabolism. Dev Cell. 2009;16:167–79.

    Article  CAS  PubMed  Google Scholar 

  39. Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–10.

    CAS  PubMed  Google Scholar 

  40. Elia L, Quintavalle M, Zhang J, Contu R, Cossu L, Latronico MV, et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ. 2009;16:1590–8.

    Article  CAS  PubMed  Google Scholar 

  41. Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, et al. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010;29:1787–97.

    Article  CAS  PubMed  Google Scholar 

  42. Kawashima H, Numakawa T, Kumamaru E, Adachi N, Mizuno H, Ninomiya M, et al. Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression. Neuroscience. 2010;165:1301–11.

    Article  CAS  PubMed  Google Scholar 

  43. Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA. 2009;106:3507–12.

    Article  CAS  PubMed  Google Scholar 

  44. Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity. 2009;31:965–73.

    Article  CAS  PubMed  Google Scholar 

  45. Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–30.

    Article  CAS  PubMed  Google Scholar 

  46. Gupta S, Purcell NH, Lin A, Sen S. Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy. J Cell Biol. 2002;159:1019–28.

    Article  CAS  PubMed  Google Scholar 

  47. Hammar EB, Irminger JC, Rickenbach K, Parnaud G, Ribaux P, Bosco D, et al. Activation of NF-kappaB by extracellular matrix is involved in spreading and glucose-stimulated insulin secretion of pancreatic beta cells. J Biol Chem. 2005;280:30630–7.

    Article  CAS  PubMed  Google Scholar 

  48. Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, et al. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008;135:257–69.

    Article  CAS  PubMed  Google Scholar 

  49. Nagaraja TN, Keenan KA, Brown SL, Fenstermacher JD, Knight RA. Relative distribution of plasma flow markers and red blood cells across BBB openings in acute cerebral ischemia. Neurol Res. 2007;29:78–80.

    Article  PubMed  Google Scholar 

  50. Rallidis LS, Vikelis M, Panagiotakos DB, Rizos I, Zolindaki MG, Kaliva K, et al. Inflammatory markers and in-hospital mortality in acute ischaemic stroke. Atherosclerosis. 2006;189:193–7.

    Article  CAS  PubMed  Google Scholar 

  51. Smith CJ, Emsley HC, Vail A, Georgiou RF, Rothwell NJ, Tyrrell PJ, et al. Variability of the systemic acute phase response after ischemic stroke. J Neurol Sci. 2006;251:77–81.

    Article  CAS  PubMed  Google Scholar 

  52. Altamura C, Squitti R, Pasqualetti P, Gaudino C, Palazzo P, Tibuzzi F, et al. Ceruloplasmin/transferrin system is related to clinical status in acute stroke. Stroke. 2009;40:1282–8.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang J, Rui YC, Yang PY, Lu L, Li TJ. C-reactive protein induced expression of adhesion molecules in cultured cerebral microvascular endothelial cells. Life Sci. 2006;78:2983–8.

    Article  CAS  PubMed  Google Scholar 

  54. Kuhlmann CR, Librizzi L, Closhen D, Pflanzner T, Lessmann V, Pietrzik CU, et al. Mechanisms of C-reactive protein-induced blood–brain barrier disruption. Stroke. 2009;40:1458–66.

    Article  CAS  PubMed  Google Scholar 

  55. Yoldas T, Gonen M, Godekmerdan A, Ilhan F, Bayram E. The serum high-sensitive C reactive protein and homocysteine levels to evaluate the prognosis of acute ischemic stroke. Mediat Inflamm. 2007;2007:15929.

    Google Scholar 

  56. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440:1217–21.

    Article  CAS  PubMed  Google Scholar 

  57. Pichler L, Muchitsch EM, Schwarz HP. [Preclinical investigation of alpha 1-acid glycoprotein (orosomucoid)]. Wien Klin Wochenschr. 1999;111:192–8.

    CAS  PubMed  Google Scholar 

  58. Iłzecka J, Dobosz B. [Acute phase proteins: alpha-1-acid glycoprotein (AGP) and alpha-1 antichymotrypsin (ACT) in serum of patients with cerebral ischemic stroke]. Neurol Neurochir Pol. 1998;32:495–502.

    PubMed  Google Scholar 

  59. Muchitsch EM, Schwarz HP. Beneficial effect of albumin therapy attributable to alpha1-acid glycoprotein? Stroke. 2003;34:4–5. author reply 4–5.

    Article  PubMed  Google Scholar 

  60. Williams JP, Weiser MR, Pechet TT, Kobzik L, Moore Jr FD, Hechtman HB. alpha 1-Acid glycoprotein reduces local and remote injuries after intestinal ischemia in the rat. Am J Physiol. 1997;273:G1031–5.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work has been supported by research grants from the National Research Foundation and the National University of Singapore, Singapore. We thank Professor Eng H Lo from Harvard Medical School, USA for training LKY on creating the animal model.

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Correspondence to Kandiah Jeyaseelan.

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Supplementary Table 1

microRNAs expression profile. List of 331 microRNAs that were significantly expressed in our miRNA microarray. Expression values were calculated as SLR; log2 (miRNA signal intensity for MCAo rats/miRNA signal intensity for normal rats). Statistical analysis, single-factor ANOVA was carried out and only expression of p < 0.05 is listed. Only signal intensity of more than 300 was considered detectable and taken for statistical analysis. (DOC 436 kb)

Supplementary Table 2

microRNAs that were differentially regulated in rat brain following MK801 administration expression. miRNAs in bold are detected in the respective blood profile. Expression values are given as SLR. Signal log ratio [log2 (signal intensity of test/signal intensity of normal)]. +MK801, MCA occluded rats that received MK801. (DOC 284 kb)

Supplementary Table 3

microRNAs that were differentially regulated in rat blood following MK801 administration. miRNAs in bold are detected in the respective brain profile. Expression values are given as SLR. Signal log ratio [log2 (signal intensity of test/signal intensity of normal)]. +MK801, MCA occluded rats that received MK801. (DOC 204 kb)

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Lim, KY., Chua, JH., Tan, JR. et al. MicroRNAs in Cerebral Ischemia. Transl. Stroke Res. 1, 287–303 (2010). https://doi.org/10.1007/s12975-010-0035-3

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